Project Abstract Although modern therapies have dramatically improved the outlooks for people living with HIV/AIDS (PLWHA) they are unable to cure infection, leaving these individuals burdened by a lifelong commitment to expensive antiretroviral medication. It has also become clear that these treatments do not fully restore health, nor do they address the negative social issues associated with being HIV positive, including stigma and issues related to criminalization. The development of a safe and effective HIV cure would thus greatly improve the lives of PLWHA. A major obstacle to curing HIV infection is the establishment of reservoirs of hidden or `latent' virus which evade the immune system and can re-seed infection if an individual stops antiretroviral therapy. Considerable efforts are underway to attempt to purge these HIV reservoirs in the blood and in other tissues in the body where the virus is known to persist. However, an important unknown currently hangs over these efforts. HIV is known to be able to infect certain cells in the brain and it is presently not known whether or not this virus can persist for long periods of time in antiretroviral-treated individuals and re-establish spreading infection. Since many of the therapies currently being tested to eliminate HIV do not target virus in the brain, this raises the possibility that even treatments that are very effective in the blood and other tissues may not cure infection. In this study we propose using a novel mouse model of HIV infection to first determine whether or not HIV can be passed from the brain to the blood and other tissues, and then to test how long any infectious virus in the brain can persist. If the virus in the brain persists for only short period of time then it is possible that sustained antiretroviral therapy will be sufficient to eliminate this reservoir in PLWHA, however if it is more durable then other types of therapies will have to be developed. In thus study we will also test two such therapies by determining whether antibodies or killer T cells that target HIV can prevent the spread of virus from the brain, either by entering into the brain and eliminating HIV at this source, or by eliminating any `beachheads' of virus in the blood or tissues from HIV that exits the brain. Thus, our study will both lead to a better understanding of the challenge that HIV reservoirs in the brain may pose to curing HIV infection, and will test therapeutics with the potential to overcome this challenge and contribute to curing infection.